Scientists at the Karolinska Institute have sequenced the genome of a salamander, the Iberian ribbed newt, which is a full six times larger than the human genome. Among the early findings is a family of genes that can provide clues to the unique ability of salamanders to rebuild complex tissue, even body parts.

The team published its study (“Reading and Editing the Pleurodeles waltl Genome Reveals Novel Features of Tetrapod Regeneration”) in Nature Communications and believes its findings may possibly lead to the development of new regenerative strategies for humans.

“Salamanders exhibit an extraordinary ability among vertebrates to regenerate complex body parts. However, scarce genomic resources have limited our understanding of regeneration in adult salamanders. Here, we present the ~20 Gb genome and transcriptome of the Iberian ribbed newt Pleurodeles waltl, a tractable species suitable for laboratory research. We find that embryonic stem cell-specific miRNAs mir-93b and mir-427/430/302, as well as Harbinger DNA transposons carrying the Myb-like proto-oncogene have expanded dramatically in the Pleurodeles waltl genome and are co-expressed during limb regeneration. Moreover, we find that a family of salamander methyltransferases is expressed specifically in adult appendages,” write the investigators.

“Using CRISPR/Cas9 technology to perturb transcription factors, we demonstrate that, unlike the axolotl, Pax3 is present and necessary for development and that contrary to mammals, muscle regeneration is normal without [a] functional Pax7 gene. Our data provide a foundation for comparative genomic studies that generate models for the uneven distribution of regenerative capacities among vertebrates.”

This is the first time that an entire newt genome has been sequenced, an achievement that can give rise to new discoveries regarding the amphibian's ability to recreate brain neurons as well as entire body parts, note the scientists. Among the first findings are a multitude of copies of a certain microRNA (miRNA) group, which in mammals is mainly found in embryonic stem cells, but also in tumor cells, they point out in their paper.

“It will be exciting to figure out how regeneration in the adult organism reactivates embryonic genes,” says study leader András Simon, Ph.D., in the department of cell and molecular biology. “What's needed now are functional studies of these miRNA molecules to understand their function in regeneration. The link to cancer cells is also very interesting, especially bearing in mind newts' marked resistance to tumor formation.”

Even though the abundance of stem cell miRNA genes is quite surprising, it alone cannot explain how salamanders regenerate so well. Dr. Simon predicts that the explanation lies in a combination of genes unique to salamanders and how other more common genes orchestrate and control the actual regeneration process.

The group at the Institute is now engaging with other researchers to discover what can be learned from the newt genome and test new hypotheses through systematic comparisons with mammals.

“We showed ten years ago that salamanders can recreate all the cells that die in Parkinson's disease in the space of four weeks,” says Dr. Simon. “We can now delve deeply into the molecular processes underlying this ability.”

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